Monoamines play a major role in depression. The present proposal will examine this idea by evaluating neural responses in the various mouse models of depression and it will complement the human imagining studies by providing a functional approach for identifying brain areas and neural circuits that may participate in depressive-like behaviors. It will also complement the human morphology experiments by targeting multi-electrodes in mice to cortical layers in frontal cortex that have been shown to change in depressed patients. To better understand the role of monoamines in depression, we will use multi-electrode arrays to investigate changes in cortical and subcortical neuronal activity in genetically-modified mice that have norepinephrine (NE) and/or serotonin (5-HT) dysfunction. Recently, we have developed a method to record activity simultaneously from multiple single neurons in various brain areas of freely-behaving mice. With this approach, cortical and subcortical neuronal activity will be monitored in several mouse models of depression and under different behavioral and treatment conditions. Briefly, we will study vesicular monoamine transporter 2 (VMAT2) heterozygotes, glycogen synthase kinase 3b (GSK) heterozygotes, and mice carrying a polymorphism in the Tph2 gene that has been identified in depressed patients. Wild type (WT) and mutant mice will be implanted with multi-electrode arrays targeted to the dorsomediofrontal and orbitofrontal cortices, nucleus accumbens (NAc), and central and basolateral amygdala (AMY) - the same sites that imagining studies have shown to be affected in human depressed patients. Multiple electrodes will be targeted to each of these areas simultaneously and neural activity will be assessed in freely-behaving mice under baseline conditions, after exposure to chronic stress, and following treatment with anti-depressants. In addition, as many depressed patients show disturbances in wake-sleep cycles, we will also analyze brain state dynamics throughout the cycle in mice under baseline, stress, and treatment conditions. The experiments we propose will allow for the first time the integration of molecular, cellular, systems, and behavioral data within the same animal and this approach should lead to a more complete understanding of the mechanisms underlying depression.